9-132905893-G-C

Position:

chr9-132905893-G-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2BP4_ModerateBP6BS2

The NM_000368.5(TSC1):c.1685C>G(p.Ala562Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000391 in 1,612,018 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

TSC1
NM_000368.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 1.79

Variant links:

Genes affected

TSC1 (HGNC:12362): (TSC complex subunit 1) This gene is a tumor suppressor gene that encodes the growth inhibitory protein hamartin. The encoded protein interacts with and stabilizes the GTPase activating protein tuberin. This hamartin-tuberin complex negatively regulates mammalian target of rapamycin complex 1 (mTORC1) signaling which is a major regulator of anabolic cell growth. This protein also functions as a co-chaperone for Hsp90 that inhibits its ATPase activity. This protein functions as a facilitator of Hsp90-mediated folding of kinase and non-kinase clients, including TSC2 and thereby preventing their ubiquitination and proteasomal degradation. Mutations in this gene have been associated with tuberous sclerosis and lymphangioleiomyomatosis. [provided by RefSeq, May 2022]

TSC1 links:

TSC1 (HGNC:):

TSC1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TSC1. . Gene score misZ 2.3217 (greater than the threshold 3.09). Trascript score misZ 3.6986 (greater than threshold 3.09). GenCC has associacion of gene with lung lymphangioleiomyomatosis, tuberous sclerosis 1, tuberous sclerosis, tuberous sclerosis complex, lymphangioleiomyomatosis.

BP4

Computational evidence support a benign effect (MetaRNN=0.07815972).

BP6

Variant 9-132905893-G-C is Benign according to our data. Variant chr9-132905893-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 186320.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1, Benign=1}. Variant chr9-132905893-G-C is described in Lovd as [Benign].

BS2

High AC in GnomAdExome4 at 59 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC1	NM_000368.5 linkuse as main transcript	c.1685C>G	p.Ala562Gly	missense_variant	15/23	ENST00000298552.9	NP_000359.1	Q92574-1Q86WV8X5D9D2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSC1	ENST00000298552.9 linkuse as main transcript	c.1685C>G	p.Ala562Gly	missense_variant	15/23	1	NM_000368.5	ENSP00000298552.3		Q92574-1
TSC1	ENST00000490179.4 linkuse as main transcript	c.1685C>G	p.Ala562Gly	missense_variant	16/24	3		ENSP00000495533.2		A0A2R8Y6S8

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000438

AC:

AN:

250870

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135600

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000882

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000404

AC:

AN:

1459794

Hom.:

Cov.:

AF XY:

0.0000358

AC XY:

AN XY:

725836

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000513

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152224

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74372

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000676

Hom.:

Bravo

AF:

0.0000151

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Tuberous sclerosis 1

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 08, 2024	- -

Hereditary cancer-predisposing syndrome

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 02, 2021	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	May 07, 2021	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jun 22, 2021

DNA sequence analysis of the TSC1 gene demonstrated a sequence change, c.1685C>G, in exon 15 that results in an amino acid change, p.Ala562Gly. This sequence change has been described in the gnomAD database with a frequency of 0.0088% in the non-Finnish European subpopulation (dbSNP rs377185303). The p.Ala562Gly change affects a poorly conserved amino acid residue located in a domain of the TSC1 protein that is known to be functional. The p.Ala562Gly substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change does not appear to have been previously described in patients with TSC1-related disorders. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Ala562Gly change remains unknown at this time. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 25, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Uncertain

0.44

T;.;T;.;.;T;.;T;.;.;.

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.53

FATHMM_MKL

Benign

0.46

LIST_S2

Uncertain

0.88

.;D;D;D;D;.;.;.;D;D;.

M_CAP

Benign

0.062

MetaRNN

Benign

0.078

T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.47

MutationAssessor

Benign

1.4

L;.;L;.;.;L;.;L;.;.;.

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.93

N;N;N;.;.;.;.;.;.;.;.

REVEL

Benign

0.11

Sift

Benign

0.22

T;T;T;.;.;.;.;.;.;.;.

Sift4G

Benign

0.36

T;T;T;.;.;.;.;.;.;.;.

Polyphen

0.053

B;.;B;.;.;B;.;B;.;.;.

Vest4

0.22

MVP

0.60

MPC

0.51

ClinPred

0.073

GERP RS

3.1

Varity_R

0.052

gMVP

0.22

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over